Development of an Allenyne-Alkyne [4+2] Cycloaddition and its Application to Total Synthesis of Selaginpulvilin A.

A new [4+2] cycloaddition of allenyne-alkyne is developed. The reaction is believed to proceed with forming an α,3-dehydrotoluene intermediate. This species behaves as a σπ-diradical to react with a hydrogen atom donor, whereas it displays a zwitterionic reactivity toward weak nucleophiles. The efficiency of trapping α,3-dehydrotoluene depends not only on its substituents but also the trapping agents. Notable features of the reaction are the activating role of the extra alkyne of the 1,3-diyne that reacts with the allenyne moiety and the opposite mode of trapping with oxygen and nitrogen nucleophiles. Oxygen nucleophiles result in the oxygen-end incorporation at the benzylic position of the α,3-dehydrotoluene, whereas with amine nucleophiles the nitrogen-end is incorporated into the aromatic core. Relying on the allenyne-alkyne cycloaddition as an enabling strategy, a concise total synthesis of phosphodiesterase-4 inhibitory selaginpulvilin A is realized.

Ruthenabenzene: A Robust Precatalyst.

Metallaaromatics constitute a unique class of aromatic compounds where one or more transition metal elements are incorporated into the aromatic system, the parent of which is metallabenzene. One of the main concerns about metallabenzenes generally deals with the structural characterization related to their relative aromaticity compared to the carbon archetype. Transition metal-containing metallabenzenes are also implicated in certain catalytic processes such as alkyne metathesis polymerization; however, these transition metal-based metallaaromatic compounds have not been developed as a catalyst. Herein, we describe an effective strategy to generate diverse arrays of ruthenabenzenes and demonstrated them as an aromatic equivalent of the Grubbs-type ruthenium alkylidene catalysts. These ruthenabenzenes can be prepared via an enyne metathesis and metallotropic [1,3]-shift cascade process to form alkyne-chelated ruthenium alkylidene intermediates followed by spontaneous cycloaromatization. The aromatic nature of these complexes was confirmed by spectroscopic and X-ray crystallographic data, and the mechanistic pathways for the cycloaromatization process were studied by DFT calculations. These ruthenabenzenes display robust catalytic activity for metathesis and other transformations, which illustrates that metallabenzenes are not only compounds of structural and theoretical interests but also are a novel platform for new catalyst development.

Alder-ene reactions driven by high steric strain and bond angle distortion to form benzocyclobutenes.

A unique aryne-based Alder-ene reaction to form benzocyclobutene is described. In this process, the thermodynamic barrier to form a four-membered ring is compensated by the relief of the strain energy of an aryne intermediate. On the other hand, the driving force to overcome the high kinetic barrier is provided by the gearing effect of the bulky substituent at the ortho-position of the ene-donor alkene. To maximize the steric strain by the ortho-substituent, a structural element for internal hydrogen bonding is installed, which plays a crucial role for both the hexadehydro Diels-Alder and the Alder-ene reactions. DFT calculations show that the bulky hydrogen bonding element lowers the activation barrier for the Alder-ene reaction by destabilizing the intermediate, which is due to the severe bond angle distortion. The preferred formation of cis-isomers can also be explained by the extent of bond angle distortion.

Reactivity and Selectivity in the Intermolecular Alder-Ene Reactions of Arynes with Functionalized Alkenes.

The reactivity and selectivity of functionalized alkenes in intermolecular Alder-ene reactions with arynes is described. The arynes generated from bis-1,3-diynes react with various trisubstituted and 1,1-disubstituted alkenes containing hydroxyl, amino, halo, carboxyl, boronate, and 1,3-dienyl functionalities, providing product distributions with varying degrees of selectivity between Alder-ene and addition reactions. The geometry of alkenes is another important factor for the reactivity of di- and trisubstituted alkenes where the allylic hydrogen of cis-disposed alkenyl system is reactive, which is the opposite reactivity compared to the corresponding intramolecular reaction.